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WO2018163216A9 - Composés de spirooxindole en tant qu'inhibiteurs de gsk3β et leur procédé de préparation - Google Patents

Composés de spirooxindole en tant qu'inhibiteurs de gsk3β et leur procédé de préparation Download PDF

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Publication number
WO2018163216A9
WO2018163216A9 PCT/IN2018/050134 IN2018050134W WO2018163216A9 WO 2018163216 A9 WO2018163216 A9 WO 2018163216A9 IN 2018050134 W IN2018050134 W IN 2018050134W WO 2018163216 A9 WO2018163216 A9 WO 2018163216A9
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compounds
spiro
methyl
triazol
furan
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WO2018163216A1 (fr
Inventor
Prathama S MAINKAR
Mohammad Abdul SATTAR
Pitchakuntla MALLESHAM
Togapur Pavan Kumar
Divya DUSCHARLA
Ummanni RAMESH
Srivari CHANDRASEKHAR
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Council of Scientific and Industrial Research CSIR
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Priority to US16/492,359 priority patent/US11306100B2/en
Publication of WO2018163216A1 publication Critical patent/WO2018163216A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to spirooxindole compounds useful as GSK3P inhibitors and process for preparation thereof. Particularly the present invention relates to spirooxindole compounds of general formula I.
  • Z is hydrogen, halogen, hydroxy, alkoxy, cyano, nitro
  • Ring A is a five membered or six membered or seven membered optionally containing additional hetero atom in the ring
  • X is optionally CH 2
  • Ring B is triazole or cyclic amine alone or with one or more hetero atoms part of the ring and optionally substituted with one or more substituents
  • Y is hydrogen, alkoxy, aryloxy, hydroxy, ester, amide, amino, alkyl or aryl, heteroaryl, wherein these substituents are optionally substituted with one or more halogen, hydroxy, alkoxy, alkyl, aryl, heteroaryl, aryloxy, nitro, cyano, ester, aldehyde,
  • substituents are further substituted with one or more halogen, hydroxy, alkoxy, alkyl, aryl, heteroaryl, aryloxy, nitro, cyano, ester, aldehyde;
  • Oxindoles substituted in the 3 position are an important structural motif among a series of natural substances and pharmaceutically effective substances. Some of these compounds exhibit biological activity against various pathogens and have e.g. antitumor or anti-HIV properties (J. Med. Chem. 2006, 49, 3432; Bioorg. Med. Chem. Lett. 2006, 16, 2105).
  • spirocyclic oxindoles are the structural motifs frequently found in many natural products and biologically active molecules. The key structural characteristic of these compounds is the spiro ring fused at the 3 -position of the oxindole core, with varying degrees of substitution around it.
  • the alkaloids such as mitraphylline, pteropodine, gelsemine, speciophylline, uncarine, Strychnofoline, Alstonisine, Rhychnophylline, Spirotriprostatin A, Salacin, Elocamine, Horsifiline, Coerulesine etc., are some of the example of natural products containing spirooxindole structural framework. Spirooxindole derivatives were found to exhibit good biological properties (PCT Patent Application No.
  • diseases related to pain such as epilepsy, anxiety, depression and bipolar disease
  • cardiovascular conditions such as arrhythmias, atrial fibrillation and ventricular fibrillation
  • neuromuscular conditions such as (restless syndrome, neuroprotection against stroke, neural trauma, and multiple sclerosis), channelopathesis such as erythromelalgia and familial rectal pain syndrome.
  • Certain spirooxindoles were also found to exhibit good analgesic and anesthetic properties (J. Med. Chem. 1976, 19, 892) and are particularly effective in treatment of chronic pain (US Pat. No. 6774132). Spirooxindole compounds are also used as aldose reductase inhibitors and are used in the treatment of diabetes. It is not surprising that these compounds have been the focus of many chemists, in part because of their biological activities, but also the challenge of the simultaneous creation of spiro-quaternary centers and multiple chiral centers. As a result, numerous elegant transformations have been developed for the effective construction of these structural skeletons (Adv. Synth. Catal. 2013, 355, 1023; Org. Lett.
  • the main objective of the present invention is to provide novel spirooxindole compounds as useful GSKSP inhibitors.
  • Another objective of the present invention is to provide the process for the preparation of novel spirooxindoles compounds.
  • the present invention affords a new class of spirooxindole of general formula I.
  • Z is hydrogen, halogen, hydroxy, alkoxy, cyano, nitro
  • Ring A is a five membered or six membered or seven membered optionally containing additional hetero atom in the ring
  • X is optionally CH 2 or none
  • Ring B is triazole or cyclic amine alone or with one or more hetero atoms part of the ring and optionally substituted with one or more substituents or no B ring present
  • Y is hydrogen, halogen, azide, alkoxy, aryloxy, hydroxy, ester, amide, amino, alkyl or aryl, heteroaryl, wherein these substituents are optionally substituted with one or more halogen, hydroxy, alkoxy, alkyl, aryl, heteroaryl, aryloxy, nitro, cyano, ester, aldehyde,
  • substituents are further substituted with one or more halogen, hydroxy, alkoxy, alkyl, aryl, heteroaryl, aryloxy, nitro, cyano, ester, aldehyde;
  • the present invention also provides a process for the preparation of spirooxindole compounds as described in the above formula
  • a large number of various spirooxindoles possessing diversely substituted architecture were found to exhibit several biological properties. These functionalities are prominent structural motifs of new medicines from different pharmacological groups.
  • the development of new structural scaffolds of spirooxindole architecture is very important for the drug discovery process. In this connection a large number of spirooxindole derivatives were developed as depicted in the above general formula I to IV.
  • the second step is protection of the free amine with Boc group.
  • the fourth step is removal of the protection on free amine.
  • the fifth step is cyclisation using iodine to give spiroiodo compounds.
  • the sixth step is conversion of iodo to azide to give spiroazide compounds.
  • the seventh step is treatment of spiroazides with alkynes to give triazole based spirooxindoles.
  • reaction of spiroiodo compounds with cyclic amines gives the cyclic amine based spirooxindoles.
  • the spirooxindole compounds prepared are tested for their efficiency towards GSIOp inhibition property and their anticancer potential.
  • Figure 1 Screening of GSIOp Inhibitors Using the ADP-Glo Kinase Assay:
  • FIG. 1 GSIOp inhibition sensitizes pancreatic cancer cells (PANC-l) to TRAIL:
  • Figure 7 Effect of AB-0 and AB-U on expression of NFkB target genes involved in cell survival:
  • Figure 8 molecules AB-0 and AB-U inhibiting cellular GSKSP sensitizing the PANC-l to TRAIL inducing apoptosis.
  • Spirooxindoles are efficient structural motifs capable of showing diverse biological activities. This resulted in design and synthesis of a large number of spirooxindoles as illustrated in Scheme 1, which comprises of:
  • oxindole (l0g,75 mmol) in dry THF (200 mL) under inert condition was added tetra methyl ethylene diamine (TMEDA) (22.5g,l50 mmol) and the resulting solution was cooled to -78 °C. After 10 min, nBuLi (60 mL, 2.5 M in hexanes) was added slowly drop by drop over 30 min, and then allowed to stir for another 30 min.
  • THF tetra methyl ethylene diamine
  • allyl bromide (l6g, 124.34 mmol) was added slowly to the reaction mixture, warmed to -23 °C, and maintained for 4h, after the completion of reaction (monitored by TLC) saturated NH 4 Cl (100 mL) was added and extracted with EtOAc (3x200 mL). The combined organic layers were washed with brine and dried over Na 2 S0 4 . The solvent was evaporated in vacuum and the residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (70:30) to give allyl oxindole (9.07g, 70% yield).
  • reaction mixture was diluted with cool water (30 mL), and extracted with diethyl ether (2x75 mL). Organic layer was washed with cool water for two times and the layers are separated. The organic layer was washed with brine (20 mL), dried over anhydrous Na 2 S0 4 and concentrated in vacuo.
  • the crude azide obtained was purified by column chromatography on silica gel eluted with hexanes/EtOAc (80:20) to give spiro-azide 7a (2.0g, 81% yield) as a pale yellow liquid.
  • reaction mixture was diluted with cool water (30 mL), and extracted with diethyl ether (2x75 mL). Organic layer was washed with cool water for two times and the layers are separated. The organic layer was washed with brine (20 mL), dried over anhydrous Na 2 S0 4 and concentrated in vacuo.
  • the crude azide obtained was purified by column chromatography on silica gel eluted with hexanes/EtOAc (80:20) to give spiro-azide 7b (2.0g, 81% yield) as a pale yellow liquid.
  • the present invention provides new class of spirooxindoles which were synthesized from oxindole.
  • GSK3p may promote tumorigenesis in many cancer types.
  • pGS levels decreased and increased levels of b-catenin confirms its stabilization due to decreased rate of proteasomal degradation.
  • Pancreatic cancer cells have already been reported to express high active pool of OdK3b Recent studies have revealed that the pancreatic cancer cells are resistant to TRAIL-induced apoptosis.
  • cytotoxicity results indicate that the compounds significantly increased sensitivity of PANC-l cells to TRAIL.
  • ⁇ dK3b inhibitors in combination with TRAIL we have analyzed cell cycle progression of proliferating PANC-l cells treated with different concentrations of compounds in the presence or absence of TRAIL. These results are in agreement with the previously reported results that the OdK3b inhibitors sensitize cancer cells to TRAIL induced cell death.
  • the docked pose of potent GSK3b with available ligands C, O, and U was predicted by Autodock tools (ADT) and Autodock 4.2.
  • the ligand coordinate file was generated using Chemdraw followed by minimization protocol, performed using steepest descent algorithm.
  • Existing co-crystal structure with defined binding site of GSK3p with PDB ID 4AFJ having 1.98A resolution was retrieved from Protein Data Bank (PDB).
  • Crystal structure was used for docking by removing the heteroatoms, hydrogen atoms and kollman charges were added to protein crystal structure using ADT.
  • the pdb files of the ligands and protein structure were converted to pdbqt file using ADT. Docking studies were concentrated on the specific binding site known as ATP binding site.
  • kinase reaction mixture was prepared by adding 5 mg of recombinant enzyme, 2 mM ATP, 1 pg of enzyme substrate along with test compound or DMSO to a final volume of 5 pl. The kinase reaction was performed by incubating the mixture at room temperature for 17 mins. To correct reaction back ground a substrate blank reaction was also performed.
  • ADP glow reagent (equal volume to reaction mixture) was added to the reaction mixture to deplete any unused ATP added to the kinase reaction and incubated at further 40 min at 27 °C. Then 10 pl of kinase detection reagent was added followed by incubation for 30 min at 27 °C to convert ADP to ATP and introduce luciferase to measure kinase activity. The luminescence was measured using luminometer (Perkin Elmer) which is directly proportional to ADP generated in kinase reaction. To determine the amount of ADP produced in kinase reaction and calculate specific activity of the enzyme, a conversion curve is prepared by serial dilution of ADP and ATP mixture. Specific activity of the GSK3P was calculated using the following equation.
  • the cell pLen,(JZ)-Top.Luc, pLen-TopFlash.dGFP 293T stable cells were generated in myoclinic USA, panc-l used in the current study were obtained from ATCC (Manassas, USA) and cultivated in DMEM (Sigma) supplemented with 10% fetal bovine serum, 100 units/mF penicillin and streptomycin. To avoid for mycoplasma contamination in cell cultures, cells were regularly tested using the MycoAlert Kit (Cambrex Bio Science Rock land, Inc., Rockland, ME, USA).
  • a reporter assay system has been established using pLenti(JZ)-Top.luc vector and HEK293T cells.
  • the stable cell lines having integrated TCF/LEF luciferase reporter gene were selected in the presence of suitable antibiotics in the culture medium.
  • stable cells were treated with different concentrations (0- 100 mM) of either compounds or standard positive controls. Cells were allowed to grow for further 24 hrs under standard culture conditions. Upon termination, cells were harvested directly in lx CC1 buffer.
  • luciferase activity was determined by measuring luminescence at wavelengths in multimode reader. The protein concentration of the lysates was estimated by Bradford assay to normalize luciferase activity with protein present in the lysates. Then the relative luciferase activity was calculated according to control cells treated with DMSO set to 1. All experiments were performed in triplicates and the mean values with ⁇ SD are presented here.
  • the plates were incubated for another 48 h in an incubator maintained at 37 °C with a constant supply of 5% C0 2 .
  • the cells were fixed using 10% TCA and incubated for 1 h at 4 °C.
  • the plates were rinsed carefully with MQ water and air dried at room temperature.
  • SRB solution was added and kept for approximately 30 min before it was rinsed off using 1% acetic acid.
  • the plates were then air dried and 100 pL of 10 mM tris base was added to each well to solubilize the SRB before absorbance was measured at 510 nm.
  • the measure of absorbance is directly proportional to cell growth and is thus used to calculate % reduction in the rate of cell proliferation according to control DMSO treated cells. All experiments were performed in triplicates; mean % age proliferation values with ⁇ SD were plotted here.
  • the compounds inhibiting GSIOp activity in-vitro added to PANC-l cells to determine their potential against intracellular GSIOp signalling pathways in cancer cells.
  • PANC-l cells were plated in 60 mm plates (100,000 cells/ 4 mL) and cultured in the standard DMEM medium containing 10% serum. After culturing for 18 hrs, different concentrations of test compounds or standard controls prepared in DMSO were added to culture media to achieve final concentration 0 to 100 mM of compound to cells. Cells were further continued to grow for 48 h with constant supply of 5% C0 2 in humid incubator. The time course (0 to 48 h) experiment was carried out simultaneously with fixed concentration of compound showing 50% growth inhibition.
  • the reaction was developed either by addition of LumiGLO substrate (Cell Signaling Technology) followed by capturing on X-ray film or addition of chromogenic NBT (nitro-blue tetrazolium chloride) and BCIP (5-bromo-4-chloro-3'-indolyphosphate p-toluidine salt) substrate for alkaline phosphatase developing purple colored bands. The blots were scanned for densitometry performed using Image-J program.
  • LumiGLO substrate Cell Signaling Technology
  • chromogenic NBT nitro-blue tetrazolium chloride
  • BCIP 5-bromo-4-chloro-3'-indolyphosphate p-toluidine salt
  • a reporter assay has been performed in the presence of identified inhibitors.
  • PANC-l cells were cultured in a 48 well plate (16000 cells/well) overnight. Following day, cells were transfected with appropriate amount NF-kB reporter construct using lipofectamine 2000 as per manufacturer’s protocol. After 16 hrs of post transfection cells were treated with identified GSK3P inhibitors and positive controls. After 48 h of treatment, cells were harvested in directly lx ccl buffer. For measuring lucif erase activity, 5 pl of cell lysate was mixed with 20 m ⁇ of assay reagent containing substrate for luciferase in MTP well plate as per manufacturer’s protocol.
  • the luciferase activity was determined by measuring luminescence at wavelengths in multimode reader.
  • the protein concentration of the lysates was estimated by Bradford assay to normalize luciferase activity with protein present in the lysates.
  • Then the relative luciferase activity was calculated according to control cells treated with DMSO set to 1. All experiments were performed in triplicates and the mean values with ⁇ SD are presented here.
  • PANC-l cells were treated with identified molecules with or without TRAIL.
  • PANC-l cell death was determined with propidium iodide (PI) uptake measured by Flow cytometry.
  • Treated cells were harvested in cold PBS and fixed in 70% ethanol at- 20 °C for overnight. The fixed cells were by centrifugation and re-suspended in PI (50 mg/mL) solution containing RNase (0.1 mg/mL) and Triton X-100 (0.05%). The cells were incubated in dark for for 1 h at room temperature.
  • PI propidium iodide
  • caspase-3 and -9 activities were measured 48 h after treating the PANC-l cells with either GSK3P inhibitors alone or in combination with TRAIL.
  • Specific fluorogenic substrates Ac-DEVD-AMC and Ac-LEHD-AFC, were used specific to Caspase-3 and -9 respectively.
  • the harvested cells were directly lysed in caspase lysis buffer (50 mM HEPES, 5mM CHAPS, 5 mM DTT, pH 7.5).
  • the lysates were mixed with respective substrates prepared standard buffer (20 mM HEPES (pH 7.5), 0.1% CHAPS, 2 mM EDTA and 5 mM DTT) and incubated for 2 hrs at 37 °C in dark.
  • the cleavage of substrates releasing AMC and AFC was detected by multimode reader (Perkin Elmer) using an excitation / emission wavelengths 380/460 nm for AMC and, 400 / 505 nm for AFC.
  • the fluorescence readings were normalized to total protein concentration. The observed fluorescence is directly proportional to activity of caspase-3 and -9.
  • the relative caspase activities were calculated as the ratio of values between DMSO treated and compound or standard drug treated cells.
  • the base agar (0.5%) was prepared by mixing equal amounts of 1% agar with 2Xmedia (20% FBS and 2x antibiotics) filled in 6-well plate. Simultaneously, PANC-l cells (l4000/well) mixed with 2X media containing different concentrations of identified compounds alone or in combination with TRAIL mixed with 0.7% of sterile agar to achieve final concentration of 0.35% top agar. The cell suspension was spread on solidified base agar.
  • the docking studies were concentrated in the specific ATP binding site, which is located between the N-terminal b-barrel domain and the C-terminal helical domain.
  • the results suggest that three compounds are binding in the ATP binding site of GSIOp (Fig A) which showed interaction with the key residue VAL135.
  • the compound C was interacting with ATP binding site of GSK3P beta pleated sheets. From the results it was observed that the presence of intermolecular H-bonding network between the CO and NH of the indole ring to the backbone NH of V135 and CO of D133 respectively.
  • the binding energy is significantly low with score -9.2 Kcal/mol.
  • GSK3P is a part of the canonical b-catenin/Wnt pathway involved in promoting cell proliferation.
  • GSIOp phosphorylates b-catenin targeting it for proteasomal degradation.
  • unphosphorylated b-catenin active form
  • HEK293T cells stably expressing tandem repeats of the TCF/LEF transcriptional response element followed by the firefly lucif erase
  • GSK glycogen synthase
  • GS glycogen synthase
  • Pancreatic cancer cells have already been reported to express high active pool of GSK ⁇ [5]. Recent studies have revealed that the pancreatic cancer cells are resistant to TRAIF-induced apoptosis [6] GSK ⁇ inhibition sensitizes pancreatic and prostate cancer cells to TRAIF mediated apoptosis [7,8].
  • PANC-l cells were treated with different concentrations of the identified compounds alone or in combination with TRAIL (10 qg/mL). The cytotoxicity results indicate that the compounds significantly increased sensitivity of PANC-l cells to TRAIL ( Figure 3 A).
  • TRAIL induced apoptosis of cancer cell is mediated by the activation of procaspases to active caspases by proteolysis.
  • the compounds show synergistic effect on activation of caspase cascade to induce apoptosis, we have measured caspase-3 and -9 activities in PANC- 1 cells treated with compounds along with TRAIL.
  • the obtained result suggests that the combinatorial treatment of PANC-l cells is more effective even at lower concentration of the compounds than individually in activation of both the caspases ( Figure 5).
  • the apoptosis of PANC-l cells treated with GSIOp inhibitors is through mitochondiral dependant pathway.
  • GSIOp is a multifunctional enzyme which phosphorylates several of its downstream substrates. GSIOp is actively involved in multiple signaling pathways thereby regulation of cell survival, proliferation, migration, inflammation, immune responses glucose regulation and insulin signaling, neuronal function and oncogenesis to embryonic development. Of the several substrates, some of the key targets are glycogen synthase, beta catenin and tau proteins [10,11]. To confirm potential of AB-0 and AB-U in combination with TRAIL on cellular GSK3P signalling, first we have measured phosphorylation of GSKSp. Increased phosphorylation of GSK3P on 9 th serine residue silences its kinase activity (Figure 6A&B).
  • GSKP participates in regulation of wnt pathway via phosphorylation of b-catenin. Active GSK3P phosphorylates b-catenin targeting it for ubiquitin mediated proteolysis. Inhibition of GSK ⁇ causes the stabilization and accumulation of b-catenin in cytoplasm and further translocates into the nucleus. Nuclear b catenin along with TCF/LEF elements continuously drive transcription of its target genes. Nuclear b-catenin is implicated in progression of several types of cancers such as prostate cancer, basal cell carcinoma, head and neck cancers and medulloblastoma.
  • NFkB is constitutively activated in most of the cancers including pancreatic cancer enhancing transcription of several genes responsible for cell survival [5] .
  • NFkB specific reporter assays To determine whether the compounds AB-0 and AB-U are NFkB dependent or independent in controlling growth of PANC-l cells we have performed NFkB specific reporter assays. As showed in figure 05, lucif erase activity that is a measure of NFkB activity is significantly decreased with dose dependent inhibition of GSKSP using AB-0 and AB-U ( Figure 7). Both the standard controls used also showed same effect in the PANC-l cells.
  • the compounds AB-0 and AB-U clearly showed synergistic effect on the BCL2 and XIAP levels.
  • both the compounds lowered expression of BCL2 and XIAP more effectively than TRAIL alone or compound alone.
  • Shadi Mamaghani et al reported that cells over expressing the BCL2 an antiapoptotic protein are resistant to TRAIL induced apoptosis. Down regulation of BCL2 upon the GSK3P inhibition may sensitize the cells to TRAIL.
  • Cyclin Dl is a cell cycle regulating protein involved in control of cancer cell proliferation.
  • Glycogen Synthase Kinase 3b is a serine/threonine kinase. It is a multi-functional enzyme, regulating several proteins involved in various signalling pathways including transcription factors, cell cycle/survival regulators and proto-oncogenes. Recent studies suggest that GSK3p may promote tumorigenesis in many cancer types. Its abberent over expression was found in human pancreatic (H), colon(I), prostate(J), leukaemia (K), thyroid(l), brain(M) and ovarian(N) cancer cells. Billadeau et. al.
  • GSK3P is significantly over expressed and active GSK3P promotes proliferation of ovarian cancer cells (N). This led to the current study design aiming to identify new GSK3P selective inhibitors and its inhibition is an attractive approach for effective treatment of pancreatic cancer.
  • Chemotherapeutic drugs are also known to be toxic to normal healthy cells which is why it has become prerequisite in present time to develop effective strategies that increase the target based therapeutic potential of anticancer drugs with decreased toxicity to normal healthy cells, more efforts are being directed towards combination chemotherapy.
  • Tumor necrosis factor-related apoptosis-inducing ligand TRAIL
  • TRAIL Tumor necrosis factor-related apoptosis-inducing ligand
  • McConkey et al were measured the TRIAL dependent apoptosis in panel of 9 pancreatic cancer cells among them PANC-l was shown to be less sensitivity to trail mediated apoptosis in our study we measured growth inhibitory effects of new GSK3 inhibitors in combination with trail (10 ng/mL), based on our data there was significant decrease in cell viability was observed in combination with TRAIL.
  • GSK3 also plays a role in cell proliferation and apoptosis through several pathways. GSK regulates the various transcription factors which initiate the transcription of several proto oncogens. Present reports revealing that GSK3 positively regulates NFkB -dependent genes responsible for proliferation and anti-apoptotic signals in many cancers like pancreatic(d), and leukemia(K). In order to conform the above findings we measured the NFKB activity upon GSK3 inhibition, as we presented in figure 8 NFKB activity was increased. Further we have measured the expression of NFKB target genes whose were involved in apoptosis and cell proliferation. Both genes bcl2 and xiap were decreased in a dose dependent manner of AB-O and AB-U.
  • nfkb positively regulates the transcription of anti-apoptotic proteins such as XIAP, BCL-2, BCL- XL, and MCL-l in cancer cells
  • GSK mediates binding NFKB P65 subunit to the promoters of an anti-apoptotic genes BCL2 and XIAP, so inhibition of GSK reduces the expression these anti-apoptotic genes, there by inhibition of GSK sensitize the pancreatic cancer cells to trail mediated apoptosis.
  • panc-l cells were showing cell death even at 25 uM concentration of AB-0 ,AB-U and death was increased with increasing doses of GSK inhibitors and in combination with the trail.
  • caspases post exposure GSK inhibitors both caspase3 and 9 were activated.
  • GSK inhibition reduces the anchorage of independent growth cancer cells this as an important future of cancer cells.
  • the main advantage of the present invention is that it provides spirooxindole derivatives.
  • the advantage of the present invention is that it provides an efficient process for the preparation of diversely substituted novel spirooxindole derivatives.
  • Another advantage of the present invention is the use of these spirooxindole compounds as GSK3P inhibitors.
  • the spirooxindole compounds prepared are novel synthetic derivatives, which are useful as GSK3p inhibitors for their anticancer potential.

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Abstract

La présente invention concerne un composé représenté par les formules générales I utile en tant qu'inhibiteurs de GSK3β et leur potentiel anticancéreux ainsi qu'un procédé de préparation de ces spirooxindoles. Formule I dans laquelle Z représente l'hydrogène, l'halogène, l'hydroxy, l'alcoxy, cyano, nitro; le cycle A représente un hétéroatome à cinq, six ou sept chaînons contenant éventuellement un hétéroatome supplémentaire dans le cycle, X est éventuellement un cycle CH2, B est un triazole ou une amine cyclique seul ou avec une ou plusieurs hétéroatomes faisant partie du cycle et éventuellement substitué par un ou plusieurs substituants, Y représente l'hydrogène, un alcoxy, un aryloxy, un hydroxy, ester, amide, amino, alkyle ou aryle, hétéroaryle, ces substituants étant éventuellement substitués par un ou plusieurs halogène, hydroxy, alcoxy, alkyle, aryle, hétéroaryle, aryloxy, nitro, cyano, ester, aldéhyde, ces substituants étant en outre substitués par un ou plusieurs halogène, hydroxy, alcoxy, alkyle, aryle, hétéroaryle, aryloxy, nitro, cyano, ester, aldéhyde.
PCT/IN2018/050134 2017-03-10 2018-03-09 Composés de spirooxindole en tant qu'inhibiteurs de gsk3β et leur procédé de préparation Ceased WO2018163216A1 (fr)

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EP3592747A1 (fr) 2020-01-15
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